Lung cancer is the leading cause of cancer-related death in the United States in both men and women. In 2006, more than 174,470 new cases of lung cancer are estimated in the United States alone, and 162,460 of lung cancer-related death. The data reflect our lack of ability to improve survival and quality of life of the patients under current treatment strategies. Targeted therapy, a newly emerged therapeutic approach aiming key molecular abnormalities in cancer progression, has shown encouraging results, such as the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and vascular endothelial growth factor (VEGF) inhibitors for patients with lung cancer. We recently discovered that hepatoma-derived growth factor (HDGF), a mitogen for both stroma cells and epithelial cells, is frequently overexpression in non-small cell lung cancer (NSCLC), which accounts for >80% of all lung cancers, and the overexpression is strongly correlated with tumor relapse and poor survivals. We further demonstrated that HDGF is involved in malignant transformation, tumor progression, and invasion. We have developed a panel of neutralizing monoclonal antibodies against HDGF. Our preliminary data show that the antibodies are effective in inhibiting lung cancer growth in xenograft tumor models, suggesting HDGF is a novel therapeutic target. We hypothesize that HDGF is a critical factor in progression of NSCLC and a novel therapeutic target. To test the hypothesis, we proposed three specific aims in this application: In Aim 1, we will determine the role of HDGF as a prognostic marker for patients with NSCLC by analyzing expression of HDGF in primary NSCLC and correlating the expression with clinicopathologic parameters. The correlation between HDHF expression and other angiogenic factors and potential HDGF downstream molecules will also be determined. In Aim 2, we will determine the therapeutic role of HDGF neutralizing monoclonal antibodies in NSCLC xenograft models and to reveal potential mechanisms of the anti-tumor effects. We will emphasize the use of the antibodies as a single agent with limited combination to prove of principles. In Aim 3, we will verify the therapeutic effects of the HDGF neutralizing antibody based regimens in heterotransplant tumor models and to identify selective and/or predictive biomarkers for anti-HDGF based therapy. The success of the project will provide strong rationale and scientific knowledge to guide development of anti-HDGF therapy for patients with lung cancer. PUBLIC HEALTH RELEVANCE: Hepatoma-derived growth factor (HDGF) is a novel molecule important for lung cancer progression. This study will evaluate the role of HDGF as a prognostic marker for identifying lung cancer patients likely to recur or metastasize after curative surgical treatment. We will also evaluate our newly developed neutralizing monoclonal anti-HDGF antibodies for their utility as therapeutic agents in lung cancer treatment.